Nicotinic acetylcholine receptors (nAChRs) are widely distributed throughout the central (CNS) and peripheral (PNS) nervous systems. Such receptors play an important role in regulating CNS function, particularly by modulating release of a wide range of neurotransmitters, including, but not necessarily limited to, acetylcholine, norepinephrine, dopamine, serotonin, and GABA. Consequently, nicotinic receptors mediate a very wide range of physiological effects, and have been targeted for therapeutic treatment of disorders relating to cognitive function, learning and memory, neurodegeneration, pain, inflammation, psychosis, sensory gating, mood, and emotion, among other conditions.
Many subtypes of the nAChR exist in the CNS and periphery. Each subtype has a different effect on regulating the overall physiological function. Typically, nAChRs are ion channels that are constructed from a pentameric assembly of subunit proteins. At least 12 subunit proteins, α2-α10 and β2-β4, have been identified in neuronal tissue. These subunits provide for a great variety of homomeric and heteromeric combinations that account for the diverse receptor subtypes. For example, the predominant receptor that is responsible for high affinity binding of nicotine in brain tissue has composition (α4)2(β2)3 (the α4β2 subtype), while another major population of receptors is comprised of homomeric (α7)5 (the α7 subtype) receptors.
Certain compounds, like the plant alkaloid nicotine, interact with all subtypes of the nAChRs, accounting for the profound physiological effects of this compound. While nicotine has been demonstrated to have many beneficial properties, not all of the effects mediated by nicotine are desirable. For example, nicotine exerts gastrointestinal and cardiovascular side effects that interfere at therapeutic doses, and its addictive nature and acute toxicity are well-known. Ligands that are selective for interaction with only certain subtypes of the nAChR offer potential for achieving beneficial therapeutic effects with an improved margin for safety.
The α7 and α4β2 nAChRs have been shown to play a significant role in enhancing cognitive function, including aspects of learning, memory and attention (Levin, E. D., J. Neurobiol. 53: 633-640, 2002). For example, α7 nAChRs have been linked to conditions and disorders related to attention deficit disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, Alzheimer's disease (AD), mild cognitive impairment, senile dementia, dementia associated with Lewy bodies, dementia associated with Down's syndrome, AIDS dementia, and Pick's disease, as well as inflammations. The α4β2 receptor subtype is implicated in attention, cognition, epilepsy, and pain control (Paterson and Norberg, Progress in Neurobiology 61 75-111, 2000), as well as smoking cessation or nicotine withdrawal syndrome.
The activity at both α7 and α4β2 nAChRs can be modified or regulated by the administration of subtype selective nAChR ligands. The ligands can exhibit antagonist, agonist, or partial agonist properties. Compounds that function as allosteric modulators are also known.
Although compounds that nonselectively demonstrate activity at a range of nicotinic receptor subtypes including the α4β2 and α7 nAChRs are known, it would be beneficial to provide compounds that interact selectively with α7-containing neuronal nAChRs, α4β2 nAChRs, or both α7 and α4β2 nAChRs compared to other subtypes.
Recently, azaadamantane derivatives have been investigated for their use as compounds that interact selectively with α7-containing neuronal nAChRs, α4β2 nAChRs, or both α7 and α4β2 nAChRs. Examples of the azaadamantane derivatives include azaadamantane substituted with heteroaryl through an ester or ether linkage. Current synthetic routes to ester- or ether-linked azaadamantane derivatives couple an azaadamantanol intermediate, the synthesis of which is laborious and inefficient, with a halo-containing heteroaryl intermediate.
Hoggarth, J. Chem. Soc., 1163-1167 (1949) shows preparation of 2-amino-5-phenyl-1,3,4-thiadiozole from benzoylthiosemicarbazide and phosphoric acid.
U.S. Pat. No. 4,251,664, filed 24 May 1978, shows preparation of 2-Amino-5-phenyl-1,3,4-thiadiazole from benzoic acid and thiosemicarbazide using concentrated sulfuric acid. Resulting compound is useful for extracting metal from aqueous solution.
U.S. Pat. No. 5,086,503, filed 16 Aug. 1989, describes preparation of amino thiadiazoles of formula
consisting in converting the acid R1COOH or the acid chloride R1COCl into the corresponding thiosemicarbazide and in conversion thereof to cyclic form, using a dehydrating agent. The dehydrating agent can be polyphosphoric acid or methane sulfonic acid or sulfuric acid when R1 represents a phenyl group. 2-amino-5-phenyl-1,3,4-thiadiozole is an intermediate to compounds useful for treating senile dementia.
Speckamp et al., Tetrahedron, Vol. 50, No. 29, pg. 8853-8862 (1994), shows synthesis of (4s)-azaadamantanol (an intermediate for synthesis of compounds useful as pharmacologically active agents) from a bicyclic amine 3-azabicyclo[3.3.1]non-6-ene, using paraformaldehyde and formic acid.
Kimpe et al., Tetrahedron, Vol. 53, No. 31, pg. 10803-10816 (1997) shows synthesis of (E)-N-benzylidene-1-(cyclohex-3-en-1-yl)methanamine by condensing cyclohex-3-enecarbaldehyde with benzylamine to give (E)-N-(cyclohex-3-en-1-ylmethylene)-1-phenylmethanamine, followed by an isomerization reaction using potassium tert-butoxide in THF. Resulting isomerized imine is useful as an intermediate for synthesis of agriculture compounds.
U.S. Pat. No. 8,314,119, issued 20 Nov. 2012, shows synthesis of (4s)-1-azaadamantan-4-ol HCl salt from a 7-step process of: (1) Reducing 1,4-dioxaspiro[4.5]decan-8-one with TOSMIC to form 1,4-dioxaspiro[4.5]decane-8-carbonitrile; (2) Reducing resulting product with LAH to form 1,4-dioxaspiro[4.5]decan-8-ylmethanamine; (3) Cyclizing resulting product with a double-Mannich type condensation using paraformaldehyde and sulfuric acid to form azaadamantan-4-one; (4) Reducing the ketone group of azaadamantan-4-one to an alcohol using NaBH4 in presence of borane-THF complex to form a diastereomer mixture of 1-azaadamantan-4-ol N-borane complex; (5) Coupling resulting product with 4-chlorobenzoic acid; (6) Separating (4s) isomer by column chromatography (silica gel, using 3:1 hexanes-EtOAc), followed by removing 4-chlorobenzoic acid moiety with NaOH; and (7) Removing BH3 group with HCl giving (4s)-1-azaadamantan-4-ol HCl salt. Alternatively, the (4s)-isomer from Step (6) can be coupled with 2-chloro-5-phenyl-1,3,4-thiadiazole, giving (4s)-4-(5-Phenyl-1,3,4-thiadiazol-2-yloxy)-1-azatricyclo[3.3.1.13,7]-decane N-borane complex. Removal of borane group affords the free base, which was crystalized as a dihydrogen citrate salt. Resulting ether-linked azaadamantane derivative is useful for treating diminished CNS function associated with traumatic brain injury or treating conditions such as arthritis or osteoarthritic pain.
U.S. Pat. No. 8,163,916, issued 24 Apr. 2012, shows synthesis of (4s)-1-azaadamantan-4-ol HBr salt, from a multi-step process of: (1) Reducing a ketone group of azaadamantan-4-one to an alcohol using NaBH4 in presence of borane-THF complex to form a diastereomer mixture of 1-azaadamantan-4-ol N-borane complex; (2) Coupling resulting product with 4-chlorobenzoic acid; (3) Separating (4s) isomer by column chromatography (silica gel, using 3:1 hexanes-EtOAc), followed by removing 4-chlorobenzoic acid moiety with NaOH; (4) Removing BH3 group with HCl giving (4s)-1-azaadamantan-4-ol in free base form; and (5) Converting free base into HBr salt by treating with HBr in dioxane. Resulting (4s)-1-azaadamantan-4-ol HBr salt is an intermediate to ester-linked azaadamantane derivatives useful for treating diminished CNS function associated with traumatic brain injury or treating inflammatory pain.
U.S. Pat. No. 7,902,222, published 30 Jul. 2009, shows synthesis of 2-bromo-5-phenyl-1,3,4-thiadiazole from 2-amino-5-phenyl-1,3,4-thiadiazole using MeCN, CuBr2 and iso-amyl nitrite. Resulting compound is an intermediate to compounds useful for treating inflammation and rheumatoid arthritis.